A: DILI is caused by either prescription or over-the-counter medications, herbal and dietary supplements, or other xenobiotics that result in abnormalities in liver tests or in hepatic dysfunction that cannot be explained by other etiologies. DILI is the most common cause of acute liver failure in the U.S. and one of the two most frequent reasons for clinical trial failure and drug withdrawals.
What are the challenges associated with diagnosing DILI?
Although DILI is clearly defined as being caused by drugs, the correlation between DILI and drug administration may not be clear in actual cases. Some drugs cause intrinsic hepatotoxicity in a dose-dependent manner, while others lead to idiosyncratic hepatotoxicity, which is dose-independent and unpredictable. Additionally, in some cases, liver injury might only become apparent weeks or months after a drug has been administered. Therefore, the diagnosis of DILI is mainly one of exclusion, i.e., abnormal liver function with other liver disease excluded. Monitoring a patient’s liver function after discontinuing the suspected causative drugs and/or after re-exposing a patient to these drugs can provide supporting evidence for a diagnosis of DILI. However, when considering this approach, the potential delay in patient response should still be kept in mind.
Complicating diagnosis even further are factors such as preexisting disease, drug-drug interactions, and other drug side effects. For example, the breakdown of damaged skeletal muscle known as rhabdomyolysis occurs commonly in patients taking illicit substances. In such cases, labs should not base a DILI diagnosis on tests for the standard hepatotoxic markers alanine aminotransferase (ALT) and aminotransferase (AST), because abnormal ALT/AST results could be due to muscle injury, liver injury, or both.
What can labs do to detect and monitor DILI?
First of all, laboratory tests for liver function are paramount for diagnosing hepatic injury, which includes DILI. These tests include ALT and AST to evaluate hepatocellular injury, alkaline phosphatase (ALP), γ-glutamyl transferase, and bilirubin for cholestasis, and albumin and prothrombin time for hepatic protein synthesis. The criteria for DILI diagnosis using these tests include either: ALT ≥ 5 x upper limit of normal (ULN); ALP ≥ 2 x ULN; or ALT ≥ 3 x ULN and total bilirubin ≥ 2 x ULN (this last criterion is also known as Hy’s law).
Secondly, drug screening and therapeutic drug monitoring can identify potential culprit drugs and quantify their concentrations. Immunoassays or spectrophotometric methods can qualify the most common hepatotoxic drugs. Liquid chromatography mass spectrometry (MS)-based assays can screen for common pharmaceutical drugs, illicit substances, and their metabolites to identify potential causative agents. Labs can also engage quantitative MS methods to evaluate drug concentrations accurately, which is vital for properly assessing DILI severity and guiding antidote therapy, if available.
Additionally, researchers are exploring and developing novel biomarkers for liver injury, which include microRNA(miR)-122, high mobility group box1, cytokeratin 18, and glutamate dehydrogenase, among others. MiR-122 in particular is an ideal DILI biomarker candidate, as it is predominantly and specifically expressed in the liver and makes up approximately 70% of total liver miRNA content.
Studies have verified that miR-122 is reliable and sensitive to liver injury compared to standard tests such as ALT, AST, and liver biopsy. Recent research also indicates that miR-122 increase precedes by approximately 8 hours the elevation of ALT and AST. This significantly shifts forward the detection window for DILI and could improve patient outcomes in cases where an antidote needs to be administered rapidly, such as when acetaminophen is the cause of DILI. Acetaminophen accounts for approximately 37% of acute liver failure cases in the U.S., but its antidote, N-acetyl-cysteine, is almost 100% effective if administered before hepatotoxicity sets in.
As technical advances simplify the process of testing for miR-122 via reverse transcription polymerase chain reaction, miR-122 and other similar biomarkers likely will soon be introduced in clinical practice to improve the diagnosis of DILI.
Jada (Yu) Zhang, MD, PhD, is a clinical chemistry and toxicology fellow at Zuckerberg San Francisco General Hospital and the University of California, San Francisco. +Email: [email protected]